Pharmacokinetics of Itraconazole and Its Main Metabolite, 7-Hydroxyitraconazole, after the Intravenous and Oral Administration to Rats with Diabetes Mellitus Induced by Streptozotocin

Abstract

It has been reported that the protein expression and mRNA level of hepatic cytochrome P450 (CYP) 3A1/2 increased in a rat model of diabetes mellitus induced by streptozotocin (DMIS rats). From this thesis, it has been obtained that 7-hydroxyitraconazole, a main metabolite of itraconazole, was formed via hepatic CYP3A1/2 in rats, and the protein expression of intestinal CYP3A subfamily was comparable between control and DMIS rats. The fungal infection was common in older patients with diabetes mellitus. Thus, itraconazole was chosen using DMIS rats as an animal model in the present thesis. After the intravenous administration of itraconazole, the AUC 0−24 hs of both itracoanzole and 7-hydroxyitracoanzole were comparable between control and DMIS rats. This could have been supported by comparable hepatic CLints for the disappearance of itraconazole and in the formation of 7-hydroxyitraconazole and comparable free fractions of itraconazole in rat plasma between two groups of rats. After the oral administration of itraconazole, the AUC 0-24 hs of both itracoanzole and 7-hydroxyitracoanzole were also comparable between control and DMIS rats. This could have been due to the comparable intestinal CLints for the disappearance of itraconazole and in the formation of 7-hydroxyitraconazole and comparable free fractions of itraconazole in rat plasma between two groups of rats. Metabolism of itraconazole and formation of 7-hydroxyitraconazole were mediated via CYP 3A1/2 in rats. The Vsss of itraconazole in troleatndomycin-treated (TMT) and dexamethasone phosphate-treated (DXT) rats were significantly smaller than respective controls. This could be due to the significantly smaller free fractions of itraconazole in the plasma than controls. Itraconazole is administered orally to the patients. If the present rat data could be extrapolated to humans, changes in the dosage regimen of oral itraconazole would not appear to be required in diabetic patients.;본 석사학위 논문에서는 itraconazole을 당뇨 rat 모델인 DMIS rat과 그 대조군 rat에 정맥과 경구로 각각 10 mg/kg씩 투여했을 때, 두 그룹간 itraconazole과 그 대사체인 7-hydroxyitraconazole의 pharmacokinetics를 비교하였다. 정맥 및 경구 투여한 뒤 itraconazole과 7-hydroxyitraconazole의 혈장 농도를 모두 24 시간까지 측정하였다. 평형 투석 방법으로 측정한 itraconazole (5 μg/ml)의 혈장 단백 결합률은 두 그룹간 서로 유사하였다 (DMIS rat; 97.9 ±0.137%, 대조군 rat; 97.9 ± 0.242%). 또한 Western blot analysis로 측정한 장 CYP3A1/2 단백 발현도 두 그룹간 유의성있는 차이가 없었다. 더욱이 간 및 소장의 CYP microsome 모두에서 itraconazole 대사 및 7-hydroxyitraconazole 형성 과정의 Km, Vmax, 및 CLint 값들도 두 그룹간 유의적인 차이를 보이지 않았다. 정맥으로 itraconazole 10 mg/kg을 투여했을 때 itraconazole의 AUC0−24 h (대조군 rats; 516 ± 88.5 μg•min/ml, DMIS rats; 522 ± 171 μg•min/ml)와 7-hydroxyitraconazole의 AUC0−24 h (control rats; 207 ± 69.6 μg•min/ml, DMIS rats; 149 ± 64.8 μg•min/ml) 모두 두 그룹간 유의성 있는 차이가 없었다. 이는 itraconazole 대사 및 7-hydroxyitraconazole 생성에 있어 hepatic CLint와 itraconazole의 혈장 단백 결합률이 유사하기 때문이다. Rat에서 itraconazole은 간 추출율이 낮은 약물이며, 간 초회통과는 미미하다. 위의 결과는 DMIS rat에서 간 CYP3A1/2의 단백 발현 및 mRNA level이 높아져도 대조군과 DMIS 군에서 itraconazole의 간 대사에는 차이가 없음을 말해준다. 경구로 itraconazole 10 mg/kg을 투여했을 때 itraconazole의 AUC0−24 h (대조군 rats; 345 ± 94.3 μg•min/ml, DMIS rats; 308 ± 154 μg•min/ml)와 7-hydroxyitraconazole의 AUC0−24 h (control rats; 362 ± 131 μg•min/ml, DMIS rats; 374 ± 181 μg•min/ml) 모두 두 그룹간 유의적인 차이를 나타내지 않았다. 장 CYP3A1/2 단백 발현이 두 그룹간 유사하고, 그리고 장 CLint값 및 itraconazole의 단백결합이 대조군과 DMIS 군에서 차이가 없는 점을 통해 이를 설명할 수 있다. Itraconazole은 환자에게 주로 경구로 투여한다. 따라서 만약 본 rat 결과를 사람에게 응용할 수 있다면, 당뇨병 환자에게 경구 itraconazole의 dosage regimen을 변경할 필요가 없을 것으로 판단된다.